Pharmaceutical compounds

Abstract

The invention provides a compound of the formula (1):or a salt, solvate, N-oxide or tautomer thereof;wherein either R1 is R1a and R2 is R2a; or R1 is R1b and R2 is R2b; provided that in each case at least one of R1 and R2 is other than hydrogen;R1a and R2a are the same or different and each is selected from hydrogen, C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl wherein the C1-4 alkyl is optionally substituted by C1-2 alkoxy;R1b and R2b are the same or different and are selected from hydrogen, C(O)NR4R5, C(O)R6 and C(O)OR6 where R6 is C1-4 alkyl, R4 and R5 are both C1-4 alkyl, or NR4R5 forms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member selected from O, N or S and oxidized forms of N and S, the heterocyclic ring being optionally substituted by one or two C1-4 alkyl groups and / or one or two oxo groups; andR3 is a group D:wherein the asterisk denotes the point of attachment to the isoindoline ring;but excluding acetic acid 5-acetoxy-4-isopropyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindole-2-carbonyl]-phenyl ester.

Description

INCORPORATION BY REFERENCE[0001]This application is a continuation-in-part application of international patent application Serial No. PCT / GB2009 / 050358 filed 9 Apr. 2009, which published as PCT Publication No. WO 2009 / 125230 on 15 Oct. 2009, which claims benefit of U.S. provisional patent application No. 61 / 044,256 filed 11 Apr. 2008 and United Kingdom patent application number 0806527.8 filed 11 Apr. 2008, the contents of both of which are incorporated herein by reference in their entirety.[0002]The foregoing applications, and all documents cited therein or during their prosecution (“appln cited documents”) and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein (“herein cited documents”), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by re...

AI Technical Summary

Benefits of technology

[0221]As used herein, the term “treatment” and the related terms “treat” and “treating” refer to both prophylactic or preventative treatment as well as curative or palliative treatment of pain. Thus, the term encompasses situations where pain is already being experienced by a subject or patient, as well as situations where pain is not currently being experienced but is expected to arise. The term “treatment”, “treat”, “treating” and related terms also cover both complete and partial pain reduction or prevention. Thus, for example, the compounds of the invention may prevent existing pain from worsening, or they reduce or even eliminate pain. When used in a prophylactic sense, the compounds may prevent any pain from developing or they may lessen the extent of pain that may develop.

[0589]An advantage of the prodrug compounds of the present invention is that they are orally administrable. Preferred prodrug compounds of the present invention provide enhanced bioavailability (compared to the parent active compound) when administered by the oral route.

Problems solved by technology

Increased genetic instability associated with the cancer phenotype leads to an increase in the production of non-native or mutant proteins.

Mutant proteins are by their nature not native and therefore have the potential to show structural instability and an increased requirement for the chaperone system.

G2 / M arrest is generally less well tolerated by the cells and consequently, they undergo apoptotic cell death.

Signal transduction inhibitors which regulate the activities of a single target, may not be as efficacious due to signalling pathway redundancy and the rapid development of resistance.

However, it is also expressed aberrantly in approximately 50% of cases of CLL, usually in those cases with unmutated B-cell receptor genes.

The thrombus may interrupt arterial blood flow, causing brain ischemia and consequent neurologic symptoms.

Ischemic stroke may also be caused by the lodging of an embolus (an air bubble) from the heart in an intracranial vessel, causing decreased perfusion pressure or increased blood viscosity with inadequate cerebral blood flow.

However, current pharmacologic therapies for treating acute stroke are limited to restoring blood flow within a narrow therapeutic time window of less than three hours after stroke.

The increased protein synthetic burden places a stress on the cell as a consequence of increased demand for energy and synthetic precursers.

Moreover, therapeutic anticancer interventions of all types necessarily increase the stresses imposed on the target tumour cells.

Whereas as many as 5-7% of drugs approved worldwide can be classified as prodrugs (Rautio (2008)), the development of pro-drugs of drugs containing phenolic hydroxyl groups has proved somewhat problematic.

However, elsewhere in the literature, it has been found that many simple dialkylcarbamate derivatives of hydroxyl compounds are too stable and too resistant to hydrolysis to function as pro-drugs (Igarashi et al., Chem. Pharm. Bull., 55(2), 328-333 (2007)—see in particular page 329 column 2).

Igarashi et al., (idem) found that the monoethylcarbamoyl derivative of a phenolic capillarisin analogue gave good plasma levels of the parent phenolic compound but that other monosubstituted carbamates were too readily hydrolysed or metabolised to be suitable as prodrugs.

Furthermore, like dialkylcarbamates, monoalkylcarbamates have also been associated with toxic side effects (Thorberg et al., idem page 2010 column 2).

Ester and ether derivatives of the phenolic dopamine autoreceptor agonist (−)-3-(hydroxyphenyl)-N-propyl-piperidine were also investigated by Thorberg et al. as potential prodrugs but they found (see page 2010 column 1) the ether and acyl ester derivatives failed to generate the parent compound in plasma, possibly because of a lack of stability and a tendency to hydrolyse while in the digestive tract.

Thus, as indicated above, the development of prodrugs for phenolic compounds is far from straightforward and functional group derivatives that may provide useful prodrug properties in one class of compounds may be ineffective or may even give rise to toxicity problems in other classes of compounds.

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